Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

Abstract The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine‐containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical C−C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N‐alkylation with formation of the pyridinium unit; the reaction proceeded site‐ and chemoselectively in the presence of an a priori more basic tertiary amine.

The spectroscopic properties of this compound were consistent with the data available in the literature. 1

3-(5-Bromopyridin-3-yl)propan-1-ol (16).
BF3•OEt2 (13.6 mL, 111 mmol) was added dropwise via syringe over 5 min to a solution of alkene 15 (20.5 g, 103 mmol) in THF (400 mL) at 0 °C in a three-necked 1-L jacketed flask equipped with addition funnel and thermometer. A freshly prepared solution of 9-borabicyclo [3.3.1]nonane (0.50 M in THF, 16.4 g, 134 mmol) was added dropwise via the addition funnel over 40 min at such a rate that the internal temperature remained at approximately 2 °C. After complete addition, the funnel was rinsed with THF (10 mL) and the thermometer was replaced with a glass stopper. The orange, homogeneous solution was stirred at 0 °C for 1 h, warmed to 10 °C and stirred for another hour, before the mixture was warmed to 20 °C and stirred at this temperature for 18 h. The by then cloudy solution was treated with anhydrous N,N,N′,N′-tetramethylethylenediamine (8.52 mL, 56.8 mmol) and cooled to 0 °C. The stopper was replaced S4 with a thermometer before aq. NaOH (3 M, 100 mL) was added dropwise over 40 min, maintaining the rate of addition such that the internal temperature remained at approximately 2 °C. During the addition, the color of the solution changed from yellow to orange-red. aq. H2O2 (75 mL, 35% w/w) was added dropwise over 20 min, ensuring that the internal temperature did not rise above 15 °C. After complete addition, the mixture was warmed to room temperature and stirred for 1 h. During this time, the color changed from orange-red to beige. The mixture was transferred slowly into ice-cold sat. aq. Na2S2O3 (400 mL) to quench the excess peroxide. The aqueous mixture was then extracted with EtOAc (2 × 200 mL), and the combined organic extracts were washed with sat. aq. Na2S2O3 (

3-(5-Bromopyridin-3-yl)propanal (S1).
Dess-Martin periodinane (28.6 g, 67.5 mmol) was added portionwise over 5 min to a stirring solution of alcohol 16 (9.72 g, 45.0 mmol) in anhydrous CH2Cl2 (400 mL) at 0 °C. The resulting suspension was stirred at 0 °C for 1.5 h before it was warmed to room temperature and stirred for another 1.5 h. At this point, full consumption of the starting material was reached (as judged by 1 H NMR analysis of an aliquot), and sat. aq. NaHCO3 (150 mL) was added dropwise over 10 min, followed by sat. aq. Na2S2O4 (150 mL).
The biphasic mixture was stirred vigorously for 1 h before the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 100 mL) and the combined organic portions were washed with sat. aq.

tert-Butyl 2-oxo-3-(phenylselanyl)piperidine-1-carboxylate (S4). A freshly prepared solution of
LiHMDS (1 M in THF, 120 mL, 120 mmol) was added dropwise over 20 min via an addition funnel to a stirring solution of lactam S3 (20.0 g, 100 mmol) in THF (400 mL) at −78 °C in a 1-L three-necked jacketed flask. The resulting mixture was stirred for 1 h at −78 °C before a solution of phenylselenyl chloride (21.1 g, 110 mmol) in anhydrous THF (50 mL) was introduced over 10 min via the addition funnel (a moderate rate of addition is important to minimize the formation of the diselenated side-product; lower yields were obtained with a slower rate of addition (i.e. >20 min)). The resulting orange solution was maintained at −78 °C for 30 min before being analyzed by TLC. Upon consumption of the starting material, the mixture was warmed to 0 °C and the reaction was quenched by the dropwise addition of water (100 mL). EtOAc (200 mL) was introduced and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2 × 200 mL) and the combined organic extracts were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography (10 -25% EtOAc/hexanes) on silica afforded the title compound (19.5 g, 55% yield) as an orange oil. 1

S13
The spectroscopic properties of this compound were consistent with the data available in the literature. 6